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Articles by F Pagani
Total Records ( 4 ) for F Pagani
  M Pinotti , D Balestra , L Rizzotto , I Maestri , F Pagani and F. Bernardi

Our previous studies with genomic minigenes have demonstrated that an engineered small nuclear RNA-U1 (U1+5a) partially rescued coagulation factor VII (FVII) mRNA processing impaired by the 9726+5G>A mutation. Here, to evaluate the U1+5a effects on FVII function, we devised a full-length FVII splicing-competent construct (pSCFVII-wt). This construct drove in COS-1 cells the synthesis of properly processed FVII transcripts and of secreted functional FVII (23 ± 4 ng/mL), which were virtually undetectable upon introduction of the 9726+5G>A mutation (pSCFVII-9726+5a). Cotransfection of pSCFVII-9726+5a with pU1+5a resulted in a partial rescue of FVII splicing and protein biosynthesis. The level increase in medium was dose dependent and, with a molar excess (1.5x) of pU1+5a, reached 9.5% plus or minus 3.2% (5.0 ± 2.8 ng/mL) of FVII-wt coagulant activity. These data provide the first insights into the U1-snRNA–mediated rescue of donor splice sites at protein level, thus further highlighting its therapeutic implications in bleeding disorders, which would benefit even from tiny increase of functional levels.

  J. M Predmore , P Wang , F Davis , S Bartolone , M. V Westfall , D. B Dyke , F Pagani , S. R Powell and S. M. Day

Background— The ubiquitin proteasome system maintains a dynamic equilibrium of proteins and prevents accumulation of damaged and misfolded proteins, yet its role in human cardiac dysfunction is not well understood. The present study evaluated ubiquitin proteasome system function in human heart failure and hypertrophic cardiomyopathy (HCM).

Methods and Results— Proteasome function was studied in human nonfailing donor hearts, explanted failing hearts, and myectomy samples from patients with HCM. Proteasome proteolytic activities were markedly reduced in failing and HCM hearts compared with nonfailing hearts (P<0.01). This activity was partially restored after mechanical unloading in failing hearts (P<0.01) and was significantly lower in HCM hearts with pathogenic sarcomere mutations than in those lacking these mutations (P<0.05). There were no changes in the protein content of ubiquitin proteasome system subunits (ie, 11S, 20S, and 19S) or in active-site labeling of the 20S proteolytic subunit β-5 among groups to explain decreased ubiquitin proteasome system activity in HCM and failing hearts. Examination of protein oxidation revealed that total protein carbonyls, 4-hydroxynonenylated proteins, and oxidative modification to 19S ATPase subunit Rpt 5 were increased in failing compared with nonfailing hearts.

Conclusions— Proteasome activity in HCM and failing human hearts is impaired in the absence of changes in proteasome protein content or availability of proteolytic active sites. These data provide strong evidence that posttranslational modifications to the proteasome may account for defective protein degradation in human cardiomyopathies.

  B Fioretti , L Catacuzzeno , L Sforna , F Aiello , F Pagani , D Ragozzino , E Castigli and F. Franciolini

The effects of histamine on the membrane potential and currents of human glioblastoma (GL-15) cells were investigated. In perforated whole cell configuration, short (3 s) applications of histamine (100 µM) hyperpolarized the membrane by activating a K+-selective current. The response involved the activation of the pyrilamine-sensitive H1 receptor and Ca2+ release from thapsigargin-sensitive intracellular stores. The histamine-activated current was insensitive to tetraethylammonium (3 mM), iberiotoxin (100 nM), and d-tubocurarine (100 µM) but was markedly inhibited by charybdotoxin (100 nM), clotrimazole (1 µM), and 1-[(2-chlorophenyl)diphenylmethyl]-1H-pyrazole (TRAM-34, 1 µM), a pharmacological profile congruent with the intermediate conductance Ca2+-activated K+ (IKCa) channel. Cell-attached recordings confirmed that histamine activated a K+ channel with properties congruent with the IKCa channel (voltage independence, 22 pS unitary conductance and slight inward rectification in symmetrical 140 mM K+). More prolonged histamine applications (2–3 min) often evoked a sustained IKCa channel activity, which depended on a La2+ (10 µM)-sensitive Ca2+ influx. Intracellular Ca2+ measurements revealed that the sustained IKCa channel activity enhanced the histamine-induced Ca2+ signal, most likely by a hyperpolarization-induced increase in the driving force for Ca2+ influx. In virtually all cells examined we also observed the expression of the large conductance Ca2+-activated K+ (BKCa) channel, with a unitary conductance of ca. 230 pS in symmetrical 140 mM K+, and a Ca2+ dissociation constant [KD(Ca)] of ca. 3 µM, at –40 mV. Notably in no instance was the BKCa channel activated by histamine under physiological conditions. The most parsimonious explanation based on the different KD(Ca) for the two KCa channels is provided.

  M Sciaccaluga , B Fioretti , L Catacuzzeno , F Pagani , C Bertollini , M Rosito , M Catalano , G D'Alessandro , A Santoro , G Cantore , D Ragozzino , E Castigli , F Franciolini and C. Limatola

The activation of ion channels is crucial during cell movement, including glioblastoma cell invasion in the brain parenchyma. In this context, we describe for the first time the contribution of intermediate conductance Ca2+-activated K (IKCa) channel activity in the chemotactic response of human glioblastoma cell lines, primary cultures, and freshly dissociated tissues to CXC chemokine ligand 12 (CXCL12), a chemokine whose expression in glioblastoma has been correlated with its invasive capacity. We show that blockade of the IKCa channel with its specific inhibitor 1-[(2-chlorophenyl) diphenylmethyl]-1H-pyrazole (TRAM-34) or IKCa channel silencing by short hairpin RNA (shRNA) completely abolished CXCL12-induced cell migration. We further demonstrate that this is not a general mechanism in glioblastoma cell migration since epidermal growth factor (EGF), which also activates IKCa channels in the glioblastoma-derived cell line GL15, stimulate cell chemotaxis even if the IKCa channels have been blocked or silenced. Furthermore, we demonstrate that both CXCL12 and EGF induce Ca2+ mobilization and IKCa channel activation but only CXCL12 induces a long-term upregulation of the IKCa channel activity. Furthermore, the Ca2+-chelating agent BAPTA-AM abolished the CXCL12-induced, but not the EGF-induced, glioblastoma cell chemotaxis. In addition, we demonstrate that the extracellular signal-regulated kinase (ERK)1/2 pathway is only partially implicated in the modulation of CXCL12-induced glioblastoma cell movement, whereas the phosphoinositol-3 kinase (PI3K) pathway is not involved. In contrast, EGF-induced glioblastoma migration requires both ERK1/2 and PI3K activity. All together these findings suggest that the efficacy of glioblastoma invasiveness might be related to an array of nonoverlapping mechanisms activated by different chemotactic agents.

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